LIQUID PHARMACEUTICAL COMPOSITION FOR ORAL USE CONTAINING 2-(4-ISOBUTYLPHENYL)PROPIONIC ACID

Abstract: A liquid pharmaceutical composition for oral use containing 2-(4-isobutylphenyl)proprionic acid, as active ingredient, and arginine is described.

Description: 'Liquid pharmaceutical composition for oral use containing 2- ( 4-i5θbutylphenyl )propionic acid" *#***##*#**#******# The present invention relates to a liquid pharmaceutical composition for oral administration containing 2-(4-isobutylphenyl)propionic acid as active ingredient, and more particularly it relates to a liquid pharmaceutical composition containing 2-(4-isobutylphenyl>- propionic acid and arginine. 2-(4-Isobutylphenyl)propionic acid, indicated herinafter with the International Nonproprietary Name Ibuprofen, is a known non-ster- oidal anti-inflammatory drug (Merck Index XI ed., n. 4812, page 476) used in therapy for its analgesic, anti-pyretic and anti-inflamma¬ tory activity. Notwithstanding Ibuprofen is used in therapy from years in racemic form, [(RS)-Ibuprofen] , it is known, for some time, that its active enantiomer is the enantiomer with (S) configuration, hereinafter referred to as (S)-Ibuprofen. Nevertheless, also the other enantiomer [(R)-Ibuprofen] aids in the pharmacological activity of the racemate since it is partially transformed into the (S) enantiomer by the organism. For a bibliographic reference on this subject see for example S.S. Adams et al., J. Phar . Pharmac. , 28., 256-257, (1976). For greater simplicity, hereinafter with the term Ibuprofen we indicate the (S) form as well as the racemic form. Liquid injectable formulations containing Ibuprofen and basic amino- acids in equimolar amounts are known. U.S. Patent 4,279,926 (SPA - Societa Prodotti Antibiotici S.p.A.) describes injectable liquid formulations containing (RS)-Ibuprofen ^ 5inate - U.S. Patent 4,877,620 (Medice Chem. Pharm. Fabrik Putter GmbH & Co. KG) describes injectable liquid formulations containing a mixture 1:1 of (S)-Ibuprofen and lysine. c There are also known solid formulations containing Ibuprofen and a molar excess of basic aminoacids, which can be used to prepare extemporaneous aqueous solutions. U.S. Patent 4,689,218 (Zambon S.p.A. ) describes an effervescent composition consisting of Ibuprofen 9-17% by weight, arginine 17-33% 0 by weight, sodium or potassium bicarbonate 20-35% by weight, sodium bitartrate 25-40% by weight. U.S. Patent 4,834,966 (Zambon S.p.A.) describes a pharmaceutical composition consisting of Ibuprofen 33-46% by weight, arginine 34-51% by weight, sodium bicarbonate 9-29% by weight. 5 However, the formulations containing Ibuprofen and basic aminoacids described in the literature are not suitable for the preparation of liquid pharmaceutical forms for oral use such as concentrated aque¬ ous solutions to be diluted in water at the moment of the adminis¬ tration. 0 In fact, liquid pharmaceutical forms for oral use, such as for example oral drops, must be chemically and physically stable for a long time, also after having been used a first time. We have now found a liquid pharmaceutical composition for oral use consisting of an aqueous solution of a mixture of arginine and 5 Ibuprofen, in a molar ratio between 1.1 and 1.5, so that the weight/volume concentration of Ibuprofen is equal to or higher than 200 mg/ml, and of optional excipients. As already reported, with the term Ibuprofen we indicate (RS)-Ibu¬ profen as well as (S ) -Ibuprofen if it is not otherwise specified. Q Preferably, L-arginine is used in the compositions object of the present invention. Still more preferably, arginine is used in a molar ratio 1.1 with respect to Ibuprofen. The excipients optionally present in the pharmaceutical composition object of the present invention are the usual excipients suitable for the preparation of liquid pharmaceutical forms for oral use to be diluted at the moment of use, such as sweetening agents, flavour¬ ing agents and preserving agents. The liquid pharmaceutical compositions object of the present inven¬ tion are characterized by a remarkable chemical and physical stabil¬ ity. The stability tests showed the absence of precipitation or degrada¬ tion phenomena assuring a constant titre of the active ingredient for at least 3 years. In particular, the liquid compositions object of the present inven¬ tion showed to be stable (i.e. with a practically constant titre of the active ingredient) after 1 year at 50°C, 40°C, 30°C and room temperature. This is particularly worth noting in the case of very concentrated aqueous solutions. Furthermore, the pharmaceutical compositions object of the present invention are characterized by a remarkable efficacy and by a rapid onset of the pharmacological effect and thus they are particularly suitable for the analgesic therapy. From a practical point of view, the liquid pharmaceutical composi¬ tions object of the present invention will be distributed into 10-50 ml bottles containing from 2 g to 20 g of Ibuprofen. For the administration, the dosage will be generally from 10 to 40 drops, to be diluted in water at the moment of use, corresponding to a single dose of Ibuprofen between 100 mg and 400 mg. In order to illustrate the present invention without limiting it, the following examples are now given. ς Example 1 L-arginine (185 g) and then (S)-Ibuprofen (200 g) were added to boiling water (1000 ml) obtaining a limpid solution. Sodium saccharine (15 g) was added. After cooling, apricot flavour (50 g) and cetylpyridinium chloride 0 (0.1 g) were added and the solution was shared into 30 ml holding bottles. The solution (1 ml corresponding to about 20 drops) had the follow¬ ing composition: (S)-Ibuprofen 200 mg L-arginine 185 mg Sodium saccharine 15 mg Apricot flavour 50 g Cetylpyridinium chloride 0.1 mg Distilled water q.s. to 1 ml. Example 2 By working in a way similar to that described in example 1 , a solu¬ tion having the following composition was prepared: (RS)-Ibuprofen 200 mg L-arginine 185 mg Sodium saccharine 15 mg Apricot flavour 50 mg Methylparaben 1.8 mg Propylparaben 0.2 mg Distilled water q.s. to 1 ml. Example 3 L-arginine (185 g) and then (S)-Ibuprofen (200 g) were added to boiling water (1000 ml) obtaining a limpid solution. Sodium saccharine (15 g) was added. After cooling, apricot flavour (50 g) and ethanol (200 g) were added and the solution was shared into 30 ml bottles. The solution (1 ml corresponding to about 20 drops) had the follow¬ ing composition: (S)-Ibuprofen 200 mg L-arginine 185 mg Sodium saccharine 15 mg Apricot flavour 50 mg Ethanol 200 mg Distilled water q.s. to 1 ml. The stability data of the above composition after 1 year at 50°C, 40°C, 30°C and room temperature are reported in the following table A. The titre of (S)-Ibuprofen was expressed as percentage (%) with respect to the starting concentration (100%). Table A Titre (%) of (S)-Ibuprofen after storage for 1 year at 50°C, 40°C, 30°C and room temperature (R.T.). (S)-Ibuprofen (%) Temperature after 1 year 50°C 100.1 40°C 100.5 30°C 100.7 R.T. 100.9 The pH value too remained practically unchanged. Example 4 By working in a way similar to that described in example 3, a solu- c tion having the following composition was prepared: (RS)-Ibuprofen 200 mg L-arginine 185 mg Sodium saccharine 15 mg Apricot flavour 50 mg Ethanol 200 mg Distilled water q.s. to 1 ml. The stability data of the above composition after 1 year at 50°C, 40°C, 30°C and room temperature are reported in the following table B. The titre of (RS)-Ibuprofen was expressed as percentage (%) with respect to the starting concentration (100%). Table B Titre (%) of (RS)-Ibuprofen after storage for 1 year at 50°C, 40°C, 30°C and room temperature (R.T.). (RS)-Ibuprofen (%) Temperature after 1 year 50°C 99.0 40°C 100.0 30°C 98.6 R.T. 100.0 The pH value too remained practically unchanged. Example 5 L-arginine (185 g) and then (S)-Ibuprofen (200 g) were added to boiling water (1000 ml) obtaining a limpid solution. After cooling, sodium bicarbonate (40 g), sodium saccharine (15 g) and apricot flavour (50 g) were added and the solution was distributed into 30 ml holding bottles. The solution has the following composition (1 ml volume correspon¬ ding to about 20 drops): (S)-Ibuprofen 200 mg L-arginine 185 mg Sodium saccharine 15 mg Sodium bicarbonate 40 mg Apricot flavour 50 mg Distilled water q.s. to 1 ml. The stability data of the above composition after 1 year at 50°C, 40°C, 30°C and room temperature are reported in the following table C. The titre of (S)-Ibuprofen was expressed as percentage (%) with respect to the starting concentration (100%). Table C Titre (%) of (S)-Ibuprofen after storage for 1 year at 50°C, 40°C, 30°C and room temperature (R.T.). (S) -Ibuprofen (%) Temperature after 1 year 50°C 100.8 40°C 100.4 30°C 100.1 R.T. 100.9 The pH value too remained practically unchanged. Example 6 By working in a way similar to that described in example 5, a solution having the following composition was prepared: (RS)-Ibuprofen 200 mg L-arginine 185 mg Sodium saccharine 15 mg Sodium bicarbonate 40 g Apricot flavour 50 mg Distilled water q.s. to 1 ml. The stability data of the above composition after 1 year at 50°C, 40°C, 30°C and room temperature are reported in the following table D. The titre of (RS)-Ibuprofen was expressed as percentage (%) with respect to the starting concentration (100%). Table D Titre (%) of (RS)-Ibuprofen after storage for 1 year at 50°C, 40°C, 30°C and room temperature (R.T.). (RS)-Ibuprofen (%) " Temperature after 1 year 50°C 98.6 40°C 98.6 30°C 99.5 R.T. 99.8 The pH value too remained practically unchanged.

Claims: Claims 1 ) A liquid pharmaceutical composition for oral use consisting of an aqueous solution of a mixture of arginine and Ibuprofen, in a molar ratio between 1.1 and 1.5, so that the weight/volume concentration of Ibuprofen is equal to or higher than 200 mg/ml, and of optional excipients. 2) A pharmaceutical composition according to claim 1 wherein Ibupro¬ fen is (RS)-Ibuprofen. 3) A pharmaceutical composition according to claim 1 wherein Ibupro¬ fen is (S)-Ibuprofen. 4) A pharmaceutical composition according to claim 1 wherein argi¬ nine is L-arginine. 5) A pharmaceutical composition according to claim 1 wherein argi- nine is in a molar ratio 1.1.

Inventors: BONADEO DANIELE, GAZZANIGA ANNIBALE, STROPPOLO FEDERICO, VIGANO' LUIGI, BONADEO, DANIELE, GAZZANIGA, ANNIBALE, STROPPOLO, FEDERICO, VIGANO', LUIGI
Applicants: BONADEO DANIELE, GAZZANIGA ANNIBALE, STROPPOLO FEDERICO, VIGANO LUIGI, ZAMBON SPA, BONADEO, DANIELE, GAZZANIGA, ANNIBALE, STROPPOLO, FEDERICO, VIGANO', LUIGI, ZAMBON GROUP S.P.A.
Application year: 1994
Main classification: A61K31
IPC codes: A61K9, A61K31